Summary In the past decade extensive research has shown that about one in three persons with schizophrenia have high levels of anti-gliadin antibodies of the IgG type (AGA IgG). This gluten sensitive group could represent an as-yet-unrecognized etiology. In the past, removing gluten from the diet has been shown to diminish or eliminate schizophrenia symptoms in dramatic case reports and small clinical trials, but not consistently. The ability to screen for AGA IgG was not well developed until the 1990's, so that not a single one of the previous gluten-free diet trials screened schizophrenia patients for AGA IgG, meaning that 2/3 of the participants in these studies would have been unlikely to benefit from the gluten-free diet (GFD). We have completed 2 clinical trials (one open label, one randomized double blind placebo controlled) demonstrating that people with schizophrenia having this AGA IgG phenotype benefit from a GFD and that strong improvement in negative symptoms is linked to changes in levels of AGA IgG. We have also shown that AGA IgG is linked to both peripheral (i.e. cytokines) and central (i.e., magnetic resonance spectroscopy (MRS) neuroimaging) measures of inflammation. This application proposes a confirmatory double-blind randomized placebo- controlled trial of the effects of a GFD in an inpatient setting in people with schizophrenia or schizoaffective disorder who are positive to AGA IgG. We will screen about 600-800 persons with chart diagnosis of schizophrenia for high levels of AGA IgG, recruiting 50 who meet eligibility criteria into an inpatient unit with controlled gluten free diet (less than 15 mg of gluten per day) for five weeks. Each day the experimental group will receive a shake containing rice flour (25 gram), and the control group an identical protein shake containing gluten flour (25 gram). We will test potential mechanisms of action linking the target engagement (AGA IgG) to symptoms via alteration in peripheral measures of immune activation (TNF-? and IL-I?) and gut permeability (zonulin and ASCA), as well as neuroimaging techniques related to neuroinflammation (MRS measures of myoinositol and total choline). Our confirmatory study will be adequately powered to establish the utility of the GFD, or to credibly demonstrate that it is not effective. If the GFD is effective, as we hypothesize, this would add a new treatment modality for schizophrenia for the first time in over half a century. In addition, the study would suggest mechanisms of action and etiologic pathways for the effects of gluten withdrawal. If this treatment is effective, it would revolutionize personalized medicine in schizophrenia by helping to define the gliadin-sensitive illness phenotype and by stimulating development of additional treatments of medications which block absorption of gluten. Negative results would redirect interest from this etiologic pathway for understanding and treatment of schizophrenia pathophysiology, and forestall unproductive GFDs in persons with schizophrenia.